A group of transforming growth factors (TGFs) have been identified in both normal and transformed cells from a variety of tissue types. These factors, which are effectors of malignant phenotypic transformation, are apparently peptides closely associated with epidermal growth factor (EGF). EGF enchances the activity of some TGFs, while others bind to the EGF receptor. This study aims to define structure-function relationships of EGF and, ultimately, TGF molecules through synthetic and chemical modification techniques, leading primarily to the rational design of effective inhibitors. Cyclic fragments of all 3 cyclic regions of EGF have been synthesized by solid phase methods, as well as complete overlapping linear and cyclic sequences. These have been tested in a variety of assays for receptor binding and biological activity. Chemically modified native EGF peptides have also been examined. A computer model of the tertiary structure of EGF has been generated and is consistent with the data obtained from the above peptides. The model will be used for designing new analogs. Efforts to prepare still larger synthetic fragments using fragment condensation techniques are planned.